Novel manganese (II)-based liver and gall specificity magnetic resonance imaging contrast agent

Abstract

The invention belongs to the technical field of preparations for in-vivo tests, and particularly relates to a novel manganese (II)-based liver and gall specificity magnetic resonance imaging contrast agent. Active components of the contrast agent comprise a manganese-based metal organic framework, ethoxybenzene and a polyethylene glycol derivative used for connecting the ethoxybenzene to the surface of the manganese-based metal organic framework. Performance evaluation shows that in a 4.5% human serum albumin (HSA) solution, the contrast agent provided by the invention shows extremely high relaxation rate of 66.4 mM <-1 > s <-1 >, which is about six times (11.2 mM <-1 > s <-1 >) of a common contrast agent Gd-EOB-DTPA under the same condition. Due to the efficient relaxation enhancement effect, the contrast agent can achieve the same imaging effect under the condition that the dosage is far lower than the traditional dosage. Specifically, only 0.025 mmol Mn < 2 + > / kg BW is needed, and the imaging contrast equivalent to that of a traditional contrast agent Gd-EOB-DTPA using 0.1 mmol Gd < 3 + > / kg BW can be achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of preparations for in vivo experiments, and specifically relates to a novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent. Background Art

[0002] Magnetic resonance imaging (MRI) is one of the most superior non-invasive diagnostic tools in modern biomedical imaging and research. Its excellent soft tissue contrast capability enables it to provide important physiological information while detecting soft tissue lesions. Primary liver cancer is one of the most common cancers worldwide, with more than 90% of cases arising from hepatocellular carcinoma (HCC), which often lacks obvious symptoms in the early stages. Most HCC patients are diagnosed at an advanced stage, highlighting the urgent need to accurately detect HCC nodules in the early stages of liver cancer development, when curative treatment options are still feasible. Unlike some cancers that require biopsy confirmation, non-invasive MRI is clinically recommended for the early diagnosis and staging of HCC, and hepatobiliary specific contrast agents are an important means to enhance the contrast between normal liver tissue and tumor lesions during the diagnostic process.

[0003] Commercial hepatobiliary specific contrast agents are mainly based on acyclic gadolinium (Gd) chelates, such as Gd-EOB-DTPA, which are relatively kinetically inert and may result in free Gd 3+ The release of Gd can cause health risks to patients with renal insufficiency, such as nephrogenic systemic fibrosis (NSF) and Gd deposition in the brain. In order to improve the stability of gadolinium-based contrast agents, the researchers used commercial macrocyclic Gd-DOTA as a template for chemical modification. Specific measures include modifying pendant side chains by aromatic substitution or introducing lipophilic benzyloxy (BnO) groups into the H4DOTA skeleton. These strategies not only achieve liver imaging contrast comparable to that of existing commercial hepatobiliary specific contrast agents, but also significantly improve the inertness of the parent complex Gd-DOTA and reduce the free Gd 3+ Risk of ion release.

[0004] At the same time, researchers are also actively exploring alternatives that do not contain gadolinium. 2+ ) is an essential trace element in living organisms and has the physical properties required for MRI applications. 2+) complexes are considered as promising alternatives. Chang, Zhu, J. Scholl et al. successfully introduced lipophilic groups into Mn-EDTA and synthesized a series of manganese-based hepatobiliary MRI contrast agents. These contrast agents consistently showed superior hepatobiliary MRI imaging capabilities. At the same time, the Caravan and Gale research groups introduced lipophilic BnO groups into Mn-PyC3A to enhance its hepatobiliary distribution. In addition, the Lu and Chang teams independently developed macrocyclic manganese complexes suitable for hepatobiliary MRI contrast agents. Fan et al. designed Mn-Fe-based ultrasmall (MnFe2O4-EOB-PEG) nanoparticles, which used multiple ligand-receptor interactions to achieve strong affinity and specificity for hepatocytes. However, although manganese-based contrast agents have shown potential as alternatives to gadolinium-based contrast agents, higher contrast agent doses are often required to achieve the same hepatobiliary MRI effects as commercial gadolinium-based contrast agents in clinical applications. Summary of the invention

[0005] In order to solve the above technical problems, the present application provides a novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent, which can achieve hepatobiliary magnetic resonance imaging effects similar to those of the commercial contrast agent Gd-EOB-DTPA at a low dose, which is specifically achieved through the following technical solutions: A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent, the active ingredients of which include a manganese-based metal organic framework, ethoxybenzene, and a polyethylene glycol derivative for connecting ethoxybenzene to the surface of the manganese-based metal organic framework; the manganese ions in the manganese-based metal organic framework have unsaturated coordination sites.

[0006] Preferably, the manganese-based metal organic framework is self-assembled from 2,5-dihydroxyterephthalic acid and divalent manganese ions.

[0007] Preferably, the polyethylene glycol derivative is an amino-modified polyethylene glycol, and both ends of the polyethylene glycol are modified with amino functional groups.

[0008] Preferably, the manganese-based metal organic framework is provided with a carboxyl functional group for reacting with the amino group at one end of the polyethylene glycol derivative.

[0009] Preferably, the process of attaching ethoxybenzene to the surface of the manganese-based metal organic framework by the polyethylene glycol derivative comprises: amidation reaction of p-aminophenol with BocNH-PEG-COOH to obtain BocNH-PEG-EOB, and then removing the Boc protecting group to obtain NH2-PEG-EOB.

[0010] Preferably, in the amidation reaction, the molar ratio of BocNH-PEG-COOH to p-aminophenol is 1:(2-3).

[0011] Preferably, the process of attaching ethoxybenzene to the surface of the manganese-based metal organic framework by the polyethylene glycol derivative further includes: the manganese-based metal organic framework Mn-MOF-74 undergoes an amidation reaction with NH2-PEG-EOB to obtain the active ingredient of the contrast agent. The molecular weight of the Mn-MOF-74 is 2000.

[0012] Preferably, the molar ratio of the manganese-based metal organic framework Mn ion to NH2-PEG-EOB is (5-6):1.

[0013] Compared with the prior art, this application has the following beneficial effects: The present application provides a novel hepatobiliary specific contrast agent, the active ingredients of which include a manganese-based metal organic framework, ethoxybenzene, and a polyethylene glycol derivative used to connect ethoxybenzene to the surface of the manganese-based metal organic framework. This design not only gives the contrast agent unique structural characteristics, but also significantly improves its performance in magnetic resonance imaging (MRI). Performance evaluation shows that in a 4.5% human serum albumin (HSA) solution, the contrast agent of the present application exhibits 66.4mM -1 s -1 The longitudinal relaxation rate is about 6 times that of the commonly used hepatobiliary specific contrast agent Gd-EOB-DTPA under the same conditions (11.2 mM -1 s -1 Due to its highly effective relaxation enhancement effect, this contrast agent can achieve the same imaging effect at a much lower dose than traditional contrast agents. Specifically, only 0.025 mmol Mn 2+ / kg BW, which is equivalent to using 0.1 mmol Gd3 + / kg BW of traditional contrast agent Gd-EOB-DTPA. In addition, lower metal concentration can further reduce the risk of heavy metal accumulation in patients, providing a safer and more effective contrast agent option for medical imaging. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] In order to clearly introduce the embodiments, the following is a brief introduction to the drawings: Figure 1 Transmission electron microscopy (TEM) images of Mn-MOF-EOB-PEG nanoparticles; Figure 2 is the hydrodynamic diameter of Mn-MOF-EOB-PEG nanoparticles; Figure 3 is the EDS spectrum of Mn-MOF-EOB-PEG nanoparticles (scale bar = 100 nm); Figure 4 Fourier transform infrared spectra (FT-IR) of Mn-MOF-EOB-PEG nanoparticles before and after modification; Figure 5 is the PXRD pattern of Mn-MOF-74; Figure 6 is the relaxivity of Mn-MOF-EOB-PEG nanoparticles in water; Figure 7 is the relaxivity of Mn-MOF-EOB-PEG nanoparticles in 4.5% human serum albumin (HSA) aqueous solution; Figure 8 Dynamic contrast-enhanced images of the liver using Mn-MOF-EOB-PEG nanoparticles; Fig. 9 Dynamic contrast-enhanced images of kidneys with Mn-MOF-EOB-PEG nanoparticles; Fig.10 is the change of the corresponding MR signal intensity of the liver (SIpost / SIpre ratio); Fig.11 is the change of the corresponding MR signal intensity of the kidney (SIpost / SIpre ratio); Fig.12 Schematic diagram of the synthesis of Mn-MOF-EOB-PEG nanoparticles; Fig.13 Coronal and transverse T1-weighted images of the liver at the HCC tumor level before and after injection of Mn-MOF-EOB-PEG; Fig.14 The contrast-to-noise ratio (CNR) values ​​of liver parenchyma to HCC tumor before and after injection of Mn-MOF-EOB-PEG. DETAILED DESCRIPTION

[0015] The present application will be further described below in the form of specific embodiments. Those of ordinary skill in the art will be able to implement the present application based on these descriptions. In addition, the embodiments of the present application involved in the following description are generally only embodiments of a part of the present application, rather than all embodiments. Therefore, based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without making creative work should fall within the scope of protection of the present application.

[0016] Example 1 A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent, the contrast agent preparation method is as follows: Synthesis of NH2-PEG-EOB. BocNH-PEG-COOH (216 mg, about 0.1 mmol), p-aminophenol (13.718 mg, 0.3 mmol) and DMTMM (27.672 mg, 0.3 mmol) were dissolved in 5 mL of methanol and reacted at room temperature for 12 h. The reaction mixture was then dialyzed with a 500 kDa dialysis bag for 8 h. The solvent was then evaporated to obtain BocNH-PEG-EOB (114 mg, about 50% yield). The Boc protecting group was then removed using DCM:TFA (3:1) to obtain NH2-PEG-EOB.

[0017] Synthesis of Mn-MOF-EOB-PEG nanoparticles, which are contrast agents. DHTP was dissolved in DMF and added dropwise to a DMF solution of Mn(OAc)2·H2O. After the reaction was completed, the supernatant was removed by centrifugation. The mixture was washed once with DMF and twice with MeOH, and then dialyzed with MeOH for 6 days, with three solvent changes, and then vacuum dried to obtain nanosized Mn-MOF-74. Subsequently, the surface of the prepared Mn-MOF-74 was modified with poly(ethylene glycol)-ethoxyphenyl, and the poly(ethylene glycol)-ethoxyphenyl ligand was adsorbed on the carboxyl groups on the surface of Mn-MOF-74 by forming an amide bond. The specific dosage ratio is as follows: Mn-MOF-74 (30.0 mg, 0.0819 mmol Mn), NH2-PEG-EOB (30 mg, 0.014 mmol) and DMTMM (4.126 mg, 0.014 mmol) were dissolved in 10 mL DMF. The reaction was carried out at room temperature for 2 h, and then the solution was dialyzed with dialysis water for 24 h, during which the solution was replaced four times. The dialyzate obtained was freeze-dried to obtain Mn-MOF-EOB-PEG nanoparticles.

[0018] Example 2 A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent, the contrast agent preparation method is as follows: Synthesis of NH2-PEG-EOB. BocNH-PEG-COOH (216 mg, about 0.1 mmol), p-aminophenol (9.14 mg, 0.3 mmol) and DMTMM (27.672 mg, 0.3 mmol) were dissolved in 5 mL of methanol and reacted at room temperature for 12 h. The reaction mixture was then dialyzed with a 500 kDa dialysis bag for 8 h. The solvent was then evaporated to obtain BocNH-PEG-EOB (114 mg, about 50% yield). The Boc protecting group was then removed using DCM:TFA (3:1) to obtain NH2-PEG-EOB.

[0019] Synthesis of Mn-MOF-EOB-PEG nanoparticles, which are contrast agents. DHTP was dissolved in DMF and added dropwise to a DMF solution of Mn(OAc)2·H2O. After the reaction was completed, the supernatant was removed by centrifugation. The mixture was washed once with DMF and twice with MeOH, and then dialyzed with MeOH for 6 days, with three solvent changes, and then vacuum dried to obtain nanosized Mn-MOF-74. Subsequently, the surface of the prepared Mn-MOF-74 was modified with poly(ethylene glycol)-ethoxyphenyl, and the poly(ethylene glycol)-ethoxyphenyl ligand was adsorbed on the carboxyl groups on the surface of Mn-MOF-74 by forming an amide bond. The specific dosage ratio is as follows: Mn-MOF-74 (25.641 mg, 0.0819 mmol Mn), NH2-PEG-EOB (30 mg, 0.014 mmol) and DMTMM (4.126 mg, 0.014 mmol) were dissolved in 10 mL DMF. The reaction was carried out at room temperature for 2 h, and then the solution was dialyzed with dialysis water for 24 h, during which the solution was replaced four times. The dialyzate obtained was freeze-dried to obtain Mn-MOF-EOB-PEG nanoparticles.

[0020] Example 3 A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent, the contrast agent preparation method is as follows: Synthesis of NH2-PEG-EOB. BocNH-PEG-COOH (216 mg, about 0.1 mmol), p-aminophenol (6.859 mg, 0.3 mmol) and DMTMM (27.672 mg, 0.3 mmol) were dissolved in 5 mL of methanol and reacted at room temperature for 12 h. The reaction mixture was then dialyzed with a 500 kDa dialysis bag for 8 h. The solvent was then evaporated to obtain BocNH-PEG-EOB (114 mg, about 50% yield). The Boc protecting group was then removed using DCM:TFA (3:1) to obtain NH2-PEG-EOB.

[0021] Synthesis of Mn-MOF-EOB-PEG nanoparticles, which are contrast agents. DHTP was dissolved in DMF and added dropwise to a DMF solution of Mn(OAc)2·H2O. After the reaction was completed, the supernatant was removed by centrifugation. The mixture was washed once with DMF and twice with MeOH, and then dialyzed with MeOH for 6 days, with three solvent changes, and then vacuum dried to obtain nanosized Mn-MOF-74. Subsequently, the surface of the prepared Mn-MOF-74 was modified with poly(ethylene glycol)-ethoxyphenyl, and the poly(ethylene glycol)-ethoxyphenyl ligand was adsorbed on the carboxyl groups on the surface of Mn-MOF-74 by forming an amide bond. The specific dosage ratio is as follows: Mn-MOF-74 (30.768 mg, 0.0819 mmol Mn), NH2-PEG-EOB (30 mg, 0.014 mmol) and DMTMM (4.126 mg, 0.014 mmol) were dissolved in 10 mL DMF. The reaction was carried out at room temperature for 2 h, and then the solution was dialyzed with dialysis water for 24 h, during which the solution was replaced four times. The dialyzate obtained was freeze-dried to obtain Mn-MOF-EOB-PEG nanoparticles.

[0022] Comparative Example 1 The hepatobiliary specific magnetic resonance imaging contrast agent of this comparative example is prepared by a method similar to that of Example 1, specifically, a polyethylene glycol derivative without an EOB group is conjugated to Mn-MOF-74, and the obtained contrast agent is Mn-MOF-PEG.

[0023] Comparative Example 2 The hepatobiliary specific magnetic resonance imaging contrast agent of this comparative example adopts the commercial contrast agent Gd-EOB-DTPA.

[0024] Performance Test 1 This performance test is performed on the Mn-MOF-EOB-PEG nanoparticle contrast agent prepared in Example 1.

[0025] The hydrodynamic diameter and size distribution of Mn-MOF-EOB-PEG nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. Figure 1 and 2 Referring to the attached figure, it can be seen that the hydrodynamic diameter of the Mn-MOF-EOB-PEG nanoparticles evaluated by dynamic light scattering (DLS) is about 250 nm. Transmission electron microscopy (TEM) imaging shows a size distribution between 50 and 150 nm.

[0026] Energy dispersive spectroscopy (EDS) was used to test the elemental composition and distribution of Mn-MOF-EOB-PEG nanoparticles. Figure 3 . Referring to the attached figure, it can be found that the nitrogen (N) signal from the PEG-EOB ligand on the surface of the nanoparticles is significant. This indicates that the PEG-EOB ligand has been successfully modified on the surface of the nanoparticles. To further confirm the structure of the contrast agent, Fourier transform infrared spectroscopy (FT-IR) was used to test the structure of the Mn-MOF-EOB-PEG nanoparticles. Figure 4 . Referring to the attached figure, it can be found that Figure 4 The characteristic bands of Mn-MOF-74 include the C=O stretching band at 1567 cm -1 , C=C stretching band at 1455 cm -1 , and the Mn-O stretching bands at 574 and 473 cm-1, which are usually located in the fingerprint region. -1 . Figure 5 Obvious features of X-ray diffraction (XRD) were observed, with peaks located at 2θ = 6.7° and 11.8°, indicating the (2 -1 0) and (2 0 0) reflections of Mn-MOF-74. These results together confirmed the successful synthesis of Mn-MOF-74 in Example 1. In addition, Figure 4 The characteristic bands of Mn-MOF-EOB-PEG in FT-IR spectrum show COC and aliphatic CH stretching bands at 1105 cm -1 and 2880 cm -1 , which correspond to EOB-PEG ligands respectively. It can be seen that EOB-PEG ligands have been successfully modified on Mn-MOF-74, and Mn-MOF-EOB-PEG nanoparticles have been successfully prepared.

[0027] Performance Test 2 This performance test was conducted on the relaxation rates of the Mn-MOF-EOB-PEG nanoparticles prepared in Example 1 and Comparative Example 1, and the results were as follows: Figure 6 and 7 . The specific test method is: Mn-MOF-EOB-PEG and Mn-MOF-PEG were dissolved in ultrapure water respectively, 200 μL of the solution was placed in each sample tube, and after preheating at 37°C for 30 minutes, the T1 and T2 relaxation times were measured using a 1.5 T desktop nuclear magnetic resonance imaging relaxation measurement system HT-MICNMR-60. The 90° pulse duration is 40s, while the 180° pulse duration is 80s. The T1 measurement was obtained by 10 inversion acquisitions with a duration between 0.05 × T1 and 5 × T2 and a repetition time of 10s. The T2 measurement used a (CPMG) pulse sequence with an echo interval of 3ms and a repetition time of 5s. The relaxation rate is defined as the reciprocal of the relaxation time (1 / T1 or 1 / T2) divided by the Mn 2+Similarly, add 50 μL of 22.5% human serum albumin (HSA) PBS solution to the corresponding sample tube, mix thoroughly, incubate at 37°C for 30 min, and then measure T1 and T2 under the same conditions to obtain r1 and r2 of the sample bound to HSA. Figure 6 and 7 It can be found that the Mn-MOF-EOB-PEG nanoparticles prepared in this application exhibit excellent relaxivity, with an r1 value of 7.3 mM -1 s -1 , which is about 2.5 times that of the clinical trial complex Mn-PyC3A. In addition, its r1 value after binding to human serum albumin (HSA) is as high as 66.4 mM -1 s -1 , far exceeding the currently commercialized liver-targeted contrast agent Gd-EOB-DTPA (11.2 mM -1 s -1 ).

[0028] Performance Test 3 In order to evaluate the in vivo imaging effect and pharmacokinetic properties of Mn-MOF-EOB-PEG as a contrast agent, physiological saline solution containing Mn-MOF-EOB-PEG nanoparticles was diluted with 0.025 mmol Mn 2+ The control group received the same concentration of comparative example 1Mn-MOF-PEG and 0.1 mmol Gd 3+ Then, the mice were subjected to dynamic contrast-enhanced scanning on a clinical 3.0 T MRI scanner to obtain T1-weighted images ( Figure 8 and 9 The normalized signal-to-noise ratio (nSNR) was used to evaluate the MRI imaging efficiency of mice ( Fig.10 and 11 ). The results showed that low doses of Mn-MOF-EOB-PEG can achieve a contrast effect comparable to that of Gd-EOB-DTPA. After injection of Mn-MOF-EOB-PEG, the liver rapidly showed an increase in brightness on T1-weighted images, reaching peak enhancement approximately 5 min after injection. The signal intensity (SI) ratio of the liver peaked at 3.04 at 5 min, which is approximately twice that of the Mn-MOF-PEG control group in the same time frame.

[0029] Performance Test 4 To quantitatively evaluate the biodistribution of Mn-MOF-EOB-PEG nanoparticles in vivo, we used inductively coupled plasma mass spectrometry (ICP-MS) to determine the concentration of Mn metal in various organs and blood of mice at different time points after intravenous injection. The results showed that Mn-MOF-EOB-PEG nanoparticles, similar to Gd-EOB-DTPA, rapidly accumulated in the liver 5 min after injection, reaching approximately 0.47 μmol Mn / g tissue. This represented approximately 68.3% of the total administered dose, while Gd(III) accounted for 52.1% of the accumulation in the liver 5 min after Gd-EOB-DTPA injection. Notably, Mn-MOF-EOB-PEG exhibited superior specificity for liver imaging. In addition, after 24 h of metabolism, the residual Mn(II) concentration in the liver was approximately 0.044 μmol / g tissue compared with the blank control group. After subtracting the blank background, the metal residue in the liver after 24 h was less than 3.4% of the total administered dose, and even less than 1% in the kidney. These results indicate that the Mn-MOF-EOB-PEG nanoparticles not only exhibit excellent liver specificity but also show efficient clearance from the liver and kidney, making them a promising Mn(II)-based hepatobiliary-specific MRI contrast agent.

[0030] Performance Test 5 To further evaluate the potential of the Mn-MOF-EOB-PEG nanoparticles prepared in Example 1 in the diagnosis of hepatocellular carcinoma (HCC), an orthotopic HCC mouse model was constructed for this performance test. Male BALB / c mice (6-8 weeks old) with normal and HCC were used in the experiment. All mice underwent MRI on a 3.0 T magnetic resonance imaging system (Ingenia Elition, Philips), which used a dedicated mouse coil and collected coronal and transverse T1-weighted images after intravenous injection of contrast agent, and the whole process lasted 40 minutes. Anesthesia was performed with Zoletil-50 (80 mg / kg) and xylitol (20 mg / kg).

[0031] Before injection, the distinction between lesion tissue and normal liver tissue in HCC mice was barely visible. However, after intravenous injection of Mn-MOF-EOB-PEG nanoparticles (dosage of 0.025 mmol Mn 2+ After 3 months, these nanoparticles rapidly accumulated in the liver, leading to the increase of Mn in tumor tissue. 2+ The concentration is significantly lower than that of normal liver tissue, providing extremely high contrast, making the location and boundaries of the tumor clearly visible (such as Fig.13 as shown).

[0032] Contrast-to-noise ratio (CNR) analysis showed that the CNR values ​​of the cross-section and coronal planes increased rapidly and reached peak values ​​at 12 and 15 minutes after the injection of Mn-MOF-EOB-PEG ( Fig.14 ). This result indicates that Mn-MOF-EOB-PEG nanoparticles can effectively enhance the MRI signal of HCC, improve the sensitivity and specificity of tumor detection, and further verify its potential application value in HCC diagnosis and imaging.

Claims

1. A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent, characterized in that: The active ingredients of the contrast agent include a manganese-based metal organic framework, ethoxybenzene, and a polyethylene glycol derivative used for connecting ethoxybenzene to the surface of the manganese-based metal organic framework; the manganese ions in the manganese-based metal organic framework have unsaturated coordination sites.

2. A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent according to claim 1, characterized in that: The manganese-based metal organic framework is self-assembled from 2,5-dihydroxyterephthalic acid and divalent manganese ions.

3. A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent according to claim 1, characterized in that: The polyethylene glycol derivative is an amino-modified polyethylene glycol, and both ends of the polyethylene glycol are modified with amino functional groups.

4. A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent according to claim 3, characterized in that: The manganese-based metal organic framework is provided with a carboxyl functional group for reacting with the amino group at one end of the polyethylene glycol derivative.

5. A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent according to claim 1, characterized in that: The process of attaching ethoxybenzene to the surface of manganese-based metal organic framework by polyethylene glycol derivatives includes: amidation reaction of p-aminophenol and BocNH-PEG-COOH to obtain BocNH-PEG-EOB, and then removing the Boc protecting group to obtain NH2-PEG-EOB.

6. A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent according to claim 5, characterized in that: In the amidation reaction, the molar ratio of BocNH-PEG-COOH to p-aminophenol is 1:(2-3).

7. A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent according to claim 5 or 6, characterized in that: The process of attaching ethoxybenzene to the surface of the manganese-based metal organic framework by the polyethylene glycol derivative also includes: the manganese-based metal organic framework Mn-MOF-74 undergoes an amidation reaction with NH2-PEG-EOB to obtain the active component of the contrast agent.

8. A novel manganese (II)-based hepatobiliary specific magnetic resonance imaging contrast agent according to claim 7, characterized in that: The molar ratio of manganese-based metal organic framework Mn ion to NH2-PEG-EOB is (5~6):1.

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